Congenital heart diseases (CHD) include a number of different anatomic malformations of the heart, together having an incidence in live-born human infants approaching 1 percent. In most affected children, the heart defect is an isolated abnormality, unaccompanied by defects in other organ systems. The same anatomic form tends to occur in members of the same family, suggesting an underlying genetic defect that is specific for the anatomic malformation. However, progress in identifying the genes involved has been slow, owing to the often complex patterns of inheritance, and the lack of large well-characterized human families with members known to have a specific anatomic form of CHD. Studies of naturally-occurring CHD in animals can provide useful models to overcome these difficulties. The common forms of CHD in dogs, as in humans, are usually isolated defects. Their clinical and anatomic features and relative frequencies closely resemble those in humans. The defective genes underlying CHD may be the same in both species: Specific anatomic forms of CHD aggregate in particular dog breeds and families, showing that the underlying genetic defect is specific for the anatomic form of CHD. Genetic and embryologic studies of canine CHD conducted under this grant have confirmed that two of the most common forms, conotruncal defects (CTD) and patent ductus arteriosus (PDA), are caused by genetic defects that interfere with specific processes in normal heart development. In initial studies, patterns of inheritance of canine CTD and PDA were complex, as in humans. However, reduction of genetic background by selective inbreeding, followed by Mendelian breeding studies revealed evidence of single gene effects, making it feasible to isolate and characterize the genes involved. Recent progress in the development of the canine genome map greatly enhance the chances of success in this endeavor. The long term aims of the proposed studies are to utilize DNA samples and phenotypic data already obtained from extensive breeding studies of canine CTD and PDA to map, clone, and characterize the genes underlying these forms of CHD. Microsatellite whole genome linkage and candidate gene studies will be used. Preliminary evidence of linkage of CTD to candidate gene regions will be pursued. These advances are expected to aid in the discovery of the corresponding molecular genetic defects in human CTD and PDA, leading to advances in genetic counseling, prenatal diagnosis, and potentially to the prevention or amelioration of these common birth defects in predisposed fetuses.